EP2117308A1 - Polymorphe und solvate eines pharmazeutikums und verfahren für ihre herstellung - Google Patents

Polymorphe und solvate eines pharmazeutikums und verfahren für ihre herstellung

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Publication number
EP2117308A1
EP2117308A1 EP08713548A EP08713548A EP2117308A1 EP 2117308 A1 EP2117308 A1 EP 2117308A1 EP 08713548 A EP08713548 A EP 08713548A EP 08713548 A EP08713548 A EP 08713548A EP 2117308 A1 EP2117308 A1 EP 2117308A1
Authority
EP
European Patent Office
Prior art keywords
amine
pyrimidin
composition
triazolo
furan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08713548A
Other languages
English (en)
French (fr)
Inventor
Slawomir Janicki
Hexi Chang
Weirong Chen
William F. Kiesman
Benjamin Lane
Richard Todd
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vernalis Research Ltd
Biogen Inc
Biogen MA Inc
Original Assignee
Vernalis Research Ltd
Biogen Idec Inc
Biogen Idec MA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vernalis Research Ltd, Biogen Idec Inc, Biogen Idec MA Inc filed Critical Vernalis Research Ltd
Publication of EP2117308A1 publication Critical patent/EP2117308A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to polymorphs and solvates of a pharmaceutical, and methods of making them.
  • Movement disorders constitute a serious health problem, especially among the elderly. These movement disorders can often be the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
  • Parkinson's disease There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per
  • Parkinson's disease 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years.
  • Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra can be destroyed before the clinical symptoms of Parkinson's disease become apparent.
  • L-dihydroxyphenylacetic acid L-DOPA
  • L-DOPA L-dihydroxyphenylacetic acid
  • DeprenylTM monoamine oxidase
  • dopamine receptor agonists e.g., bromocriptine and apomorphine
  • anticholinergics e.g., benztrophine, orphenadrine
  • Transmitter replacement therapy may not provide consistent clinical benefit, especially after prolonged treatment when "on-off" symptoms develop.
  • such treatments have also been associated with involuntary movements of athetosis and chorea, nausea and vomiting.
  • current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients.
  • SUMMARY Blocking of purine receptors may be beneficial in treatment or prevention of movement disorders such as Parkinson's disease, or disorders such as depression, cognitive, or memory impairment, acute and chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject.
  • One adenosine A 2A inhibitor is 3-(4-amino-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine.
  • a composition in one aspect, includes crystal form B of 3-(4-amino-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine (1).
  • the composition can be substantially pure crystal form B of 1.
  • the composition can be characterized by peaks in X-ray powder diffraction at 2 ⁇ of 7.64°, 10.70°, 12.23°, 21.46°, 22.25°, 22.79°, 24.25°, and 28.43°.
  • the composition can be characterized by peaks in X- ray powder diffraction at 2 ⁇ of 7.64°, 10.70°, 12.23°, 13.17°, 15.24°, 16.50°, 17.82°, 18.50°, 19.49°, 20.52°, 21.46°, 22.25°, 22.79°, 24.25°, 26.50°, 27.33°, and 28.43°.
  • the composition can further include a pharmaceutically acceptable carrier.
  • a composition in another aspect, includes a solvate of 3-(4-amino-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine.
  • the composition can include a THF solvate, a methyl ethyl ketone solvate, a 1,4-dioxane solvate, or a l,l,l,3,3,3-hexafluoropropan-2-ol solvate of 1.
  • the solvate can be substantially pure.
  • the solvate can be crystal form D of 1.
  • the solvate can be crystal form E of 1.
  • the solvate can be crystal form F of 1.
  • the solvate can be crystal form G of 1.
  • the solvate can be crystal form H of 1.
  • a method of preparing crystal form B of 1 includes contacting 1, an N-protected derivative thereof, or a combination thereof, with a sulfonic acid.
  • the sulfonic acid can be methanesulfonic acid.
  • Contacting with a sulfonic acid can include contacting with an aqueous solution of methanesulfonic acid having a concentration of 1 M or greater.
  • the N-protected derivative of 1 can be 3-(4-trifluoroacetamido-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine.
  • the method can further include contacting 1, an N-protected derivative thereof, or a combination thereof, with a basic composition.
  • the basic composition can be an aqueous potassium hydroxide solution.
  • the concentration of potassium hydroxide in the aqueous potassium hydroxide solution can be greater than 1 M.
  • a method of preparing crystal form B of 3-(4-amino-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine includes contacting 3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine with a carboxylic acid.
  • the carboxylic acid can be formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butanoic acid, or a combination thereof.
  • the method can further include contacting 3-(4-amino-3- methylbenzyl)-7-(furan-2-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine with a basic composition.
  • the basic composition can be an aqueous ammonium hydroxide solution.
  • a method of making a compound includes combining in a vessel an amount of DADCP, an amount (3-methyl-4-nitrophenyl)methanamine hydrochloride with an amount of a sterically hindered amine and an amount of high boiling point alcohol, thereby forming a reaction mixture, and heating the reaction mixture to a temperature above 100 0 C for a predetermined reaction time.
  • Heating the reaction mixture can include heating to a temperature of 120 0 C or higher.
  • the sterically hindered amine can be diisopropylethylamine (DIPEA), triisopropyl amine, triisobutyl amine, 2,4,6-collidine, 2,6-lutidine, 2,6-di-t-butylpyridine, or l,4-diazabicyclo[2.2.2]ocatane.
  • the high boiling point alcohol can be n-butanol, ethylene glycol, 1,4-butanediol, 1,3-butanediol, benzyl alcohol, t-amyl alcohol, n- pentanol, or 2-butoxyethanol.
  • the method can including adding a diazotization reagent to the reaction mixture after the predetermined reaction time.
  • the diazotization reagent can be a nitrite salt, such as sodium nitrite.
  • FIGS. IA- 1C are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 2A-2C are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 3A-3C are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 4A-4C are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 5A-5B are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 6A-6D are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIGS. 7A-7B are graphs depicting properties of a crystalline form of a pharmaceutical.
  • FIG. 8 is a graph depicting properties of a crystalline form of a pharmaceutical.
  • FIG. 9 is a schematic depiction of a crystal structure of a pharmaceutical.
  • FIG. 10 is a schematic depiction of a crystal structure of a pharmaceutical.
  • Blockade of A 2 adenosine receptors has been implicated in the treatment of movement disorders such as Parkinson's disease and in the treatment of cerebral ischemia. See, for example, Richardson, P. J. et al., Trends Pharmacol ScL 1997, 18, 338-344, and Gao, Y. and Phillis, J. W., Life ScL 1994, 55, 61-65, each of which is incorporated by reference in its entirety.
  • Adenosine A 2A receptor antagonists have potential use in the treatment of movement disorders such as Parkinson's Disease (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320, which is incorporated by reference in its entirety).
  • Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects.
  • the central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, because of the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., /. Med. Chem 1992, 35, 407-422, and Bhagwhat, S. S.; Williams, M. E. Opin. Ther. Patents 1995, 5,547-558, each which is incorporated by reference in its entirety).
  • Adenosine receptors represent a subclass (Pi) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors.
  • the main pharmacologically distinct adenosine receptor subtypes are known as Ai, A 2A , A 2B (of high and low affinity) and A 3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156, which is incorporated by reference in its entirety).
  • the adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. ScL, 1995, 10, 122-128, which is incorporated by reference in its entirety).
  • Pi receptor-mediated agents can be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707- 722; and Williams, M. and Bumnstock, G. Purinergic Approaches Exp. Ther. (1997), 3- 26. Editor. Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-liss, New York, N. Y., which is incorporated by reference in its entirety).
  • Parkinson's disease Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300
  • Baraldi P. G. et al., Curr. Med. Chem. 1995, 2, 707- 722
  • xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD).
  • ADHD attention-deficit hyperactivity disorder
  • Antagonism of adenosine receptors is thought to account for the majority of the behavioral effects of caffeine in humans and thus blockade of adenosine A 2A receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective adenosine A 2A receptor antagonist may provide an effective treatment for ADHD but with decreased side-effects.
  • Adenosine receptors can play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268, which is incorporated by reference in its entirety).
  • Adenosine's sleep regulation can be mediated by the adenosine A 2A receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996, 93: 5980-5984, which is incorporated by reference in its entirety).
  • a selective adenosine A 2A receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.
  • adenosine A 2A receptor antagonists may be useful in treatment of major depression and other affective disorders in patients.
  • a 2A receptors may be functionally linked dopamine D 2 receptors in the CNS. See, for example, Ferre, S. et al., Proc. Natl. Acad.
  • adenosine A 2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated. See, e.g., Ongini, E.; Adami, M.; Ferri,
  • adenosine A 2A receptor antagonist may confer neuroprotection in neurodegenerative diseases such as Parkinson's disease.
  • Xanthine derivatives have been disclosed as adenosine A 2A receptor antagonists for treating various diseases caused by hyperfunctioning of adenosine A 2 receptors, such as Parkinson's disease (see, for example, EP-A-565377, which is incorporated by reference in its entirety).
  • One prominent xanthine-derived adenosine A 2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett, 1993, 323, 141-144, which is incorporated by reference in its entirety).
  • Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A 1 and A 2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in
  • Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week.
  • the patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515- 517, which is incorporated by reference in its entirety).
  • KF 17837 [E-8-(3,4dimethoxystyryl)-l,3-dipropyl-7-methylxanthine] is a selective adenosine A 2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A 2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine.
  • KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A 2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268, which is incorporated by reference in its entirety).
  • SAR structure activity relationship
  • Non- xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., /. Med Chem. 1996, 39, 1164-71, which is incorporated by reference in its entirety).
  • SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2- furyl)-pyrazolo-[4,3-e]-l,2,4triazolo[l,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70, which is incorporated by reference in its entirety) and has been followed up by a later series of compounds (Baraldi, P. G. et al., /. Med. Chem. 1998,41(12), 2126-2133, which is incorporated by reference in its entirety).
  • adenosine A 2A inhibitor is 3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5-amine (1). See International Patent Application Publication WO 02/055083, which is incorporated by reference in its entirety.
  • Compound 1 can be synthesized using any conventional technique, several of which are exemplified below. Preparation of 1 is described generally in WO 02/055083 (see, e.g., pages 23-28, 42, 66-67, and 106).
  • WO 02/055083 describes the following sequence of reactions:
  • synthesis of compound 1 relies on the reaction of a tosylated pyrimidine 2 with 3-methyl-4-triflouroacetamido-benzylamine 3.
  • the final step in this route is removal of the trifluoroacetyl protecting group by basic hydrolysis.
  • synthesis of compound 1 proceeds by forming the triazole ring prior to forming the pyrimidine ring, as illustrated in the schemes below.
  • synthesis of compound 1 involves the reaction of the pyrimidine 4 with a diazonium species:
  • the synthetic method can involve the coupling of N- (2-amino-4,6-dichloropyrimidin-5-yl)-formamide with 3-methyl-4-nitrobenzamide.
  • the coupling reaction can be favored by using a sterically hindered amine and a high-boiling point alcohol as a solvent.
  • the sterically hindered amine is preferably substantially basic and substantially non-nucleophilic.
  • suitable sterically hindered amines include diisopropylethylamine (DIPEA), triisopropyl amine, triisobutyl amine, 2,4,6-collidine, 2,6-lutidine, 2,6-di-t-butylpyridine, and 1,4- diazabicyclo[2.2.2]ocatane.
  • DIPEA diisopropylethylamine
  • triisopropyl amine triisobutyl amine
  • 2,4,6-collidine 2,6-lutidine
  • 2,6-di-t-butylpyridine 1,4- diazabicyclo[2.2.2]ocatane.
  • a sterically hindered amine can be more sterically
  • the high-boiling point alcohol can have a boiling point higher than that of water (i.e., 100 0 C at atmospheric pressure).
  • suitable high-boiling point alcohols are n-butanol, ethylene glycol, 1,4- butanediol, 1,3-butanediol, benzyl alcohol, t-amyl alcohol, n-pentanol, and 2- butoxyethanol.
  • the product of the coupling reaction can be combined with a diazotization reagent (e.g., NaNC ⁇ ) in the same pot, without the need to isolate the product of the coupling reaction.
  • a diazotization reagent e.g., NaNC ⁇
  • Form A X-ray powder diffraction patterns, DSC measurements, and solvent content.
  • the various crystal forms are designated Form A, Form B, Form D, Form E, Form F, Form G, and Form H.
  • Form A can be prepared by dissolving compound 1 in a suitable solvent, such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide
  • a suitable solvent such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide
  • compound 1 can be dissolved in a mixture of a solvent, (e.g., THF, DMF, DMA, or NMP) and an antisolvent, such as water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl methyl ether (TBME), acetone, acetonitrile, 1,2-dimethoxyethane, or a mixture thereof, at a temperature suitable for dissolution of compound 1.
  • a solvent e.g., THF, DMF, DMA, or NMP
  • an antisolvent such as water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl methyl ether (TBME), acetone, acetonitrile, 1,2-dimethoxyethane, or a mixture thereof, at a temperature suitable for dissolution of compound 1.
  • An antisolvent can then be added to the mixture under conditions suitable for the formation of Form A.
  • compound 1 can be dissolved in DMSO and then combined with an alcohol, for example, methanol, ethanol, propanol, isopropanol, n-butyl alcohol, sec-butyl alcohol, or t-butyl alcohol, and, optionally, with a second anti-solvent such as an alcohol or water.
  • an alcohol for example, methanol, ethanol, propanol, isopropanol, n-butyl alcohol, sec-butyl alcohol, or t-butyl alcohol, and, optionally, with a second anti-solvent such as an alcohol or water.
  • Form A can also be prepared by dissolving compound 1 in a mixture of a solvent and an acid.
  • suitable solvents for this method include THF, ethanol, and methanol.
  • suitable acids include hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • compound 1 is then precipitated by addition a suitable base, such as a hydroxide or an amine, (for example, aqueous sodium hydroxide) under conditions suitable for the production of Form A.
  • Form B can be prepared by dissolving compound 1 in a mixture of a solvent and an acid, particularly water and methanesulfonic acid, and precipitating compound 1 by addition a suitable base, such as a hydroxide, or an amine, (e.g., aqueous potassium hydroxide) under conditions suitable for the production of Form B.
  • a suitable base such as a hydroxide, or an amine, (e.g., aqueous potassium hydroxide) under conditions suitable for the production of Form B.
  • crystal form B can be prepared by dissolving compound 1 (or a protected form, e.g., a form in which the phenyl amino group is acylated, such as with an acetyl or trifluoroacetyl group) in a solution of water and an alkyl sulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, and adding an organic solvent, such as ethyl acetate (for example, to extract any remaining protected 1), and a base, such as a hydroxide base like sodium hydroxide, potassium hydroxide, or ammonium hydroxide. Addition of the base can result in precipitation of 1.
  • the precipitate can be reslurry (e.g., in water or an aqueous solvent system) to remove any residual alkyl sulfonic acid.
  • crystal form B can be forming a slurry of compound 1 in a mixture of water and an alkyl acid, such as, for example, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butanoic acid, or the like, and neutralizing the mixture with a base, such as a hydroxide base like sodium hydroxide, potassium hydroxide, or ammonium hydroxide.
  • an alkyl acid such as, for example, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butanoic acid, or the like
  • a base such as a hydroxide base like sodium hydroxide, potassium hydroxide, or ammonium hydroxide.
  • the compound can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such
  • the compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions can include compound 1, or pharmaceutically acceptable derivatives thereof, together with any pharmaceutically acceptable carrier.
  • carrier as used herein includes acceptable adjuvants and vehicles.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, polyethylene glycol and wool fat.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
  • the pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler.
  • a nebulizer a dry powder inhaler or a metered dose inhaler.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co-administered.
  • a pharmaceutical composition can include an effective amount of compound 1.
  • An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day of the active ingredient compound are useful.
  • reaction mass was filtered and washed with an isopropyl alcohol/water mixture (140 mL/180 mL) followed by water (215.0 mL) and cold isopropyl alcohol (95.0 mL).
  • the product was dried at 40-45 0 C for 10-15 hr under vacuum to yield 150-155 g (92-95%) of N-[2-amino-4-chloro-6-(3-methyl-4-nitro- benzylamino)-pyrimidin-5-yl]-formamide.
  • DADCP 2,5-Diamino-4,6-dichloropyrimidine
  • DIPEA diisopropylethylamine
  • a IL reaction vessel was charged with 7-chloro-3-(3-methyl-4-nitrobenzyl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5-amine (50.0 g, 156.4 mmol), and Pd(dppf)Cl 2 (185 mg, 0.234 mmol). The vessel was then evacuated and flushed with nitrogen 4 times to remove oxygen. Next, triethylamine (65.4 mL, 469 mmol), degassed water (300 mL) and degassed THF (200 mL) was added via cannula. The slurried material was then heated to 68 0 C and held at that temperature for 15 minutes.
  • Example 4 Preparation of3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5-amine (1) A 250 mL 2-necked round-bottomed flask was charged with 7-(furan-2-yl)-3-(3- methyl-4-nitrobenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine (3.0 g, 8.5 mmol) and 5% Pd/C catalyst (0.46 g, 0.073 mmol) under a nitrogen atmosphere.
  • a sample of 1 in crystal form A was prepared by charging a 250 mL round bottom flask with compound 1 (10.0 g) and DMSO (45 mL) at room temperature. The resultant slurry was heated to 75 0 C to give a clear solution. Isopropanol (90 mL) was added to the solution over 2 hours at 75 0 C and then cooled to room temperature. The mixture was filtered at room temperature and washed with a DMSO/isopropanol mixture (13 mL/26 mL) followed by isopropanol (40 mL). The product was dried under vacuum to yield 9.59 g (95.9%) of the crystal form A of 1. The sample was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • a glass lined 1000 L reactor was charged with 58.3 kg wet, crude compound 1. After purging the reactor with nitrogen, the reactor was charged with 289 kg DMSO, and the mixture was heated to 77 - 83 0 C. A solution was obtained, to which 210
  • XRPD peak assignments can vary by plus or minus
  • FIG. IA shows an XRPD trace of crystal form A.
  • the XRPD pattern of crystal form A is characterized by peaks at 2 ⁇ of 7.20°, 8.14°, 10.26°, 13.00°, 14.23°, 15.10°,
  • FIG. IB shows a DSC thermogram for crystal form A.
  • Crystal form A shows a minimum in DSC thermograms (i.e., melting point) at about 243 0 C - 246 0 C, with a ⁇ H f of between 154.5 J/g and 165.8 J/g.
  • DSC analysis before and after micronisation showed no significant difference in the heat of fusion, confirming that micronisation did not adversely affect crystalline quality.
  • FIG. 1C shows a TGA trace for crystal form A.
  • TGA revealed that form A was substantially free of solvent; weight loss from ambient temperature to 220 0 C varied between ⁇ 0.1 %w/w to 1.2 %w/w.
  • TGA analysis before and after micronisation showed that micronised material contained less unbound and less trapped solvent than the pre- micronised material.
  • Example 6 Characterization of Crystal Form B ofl
  • a sample of 1 in crystal form B was prepared by charging MeSOsH (143 mL), H 2 O (1000 mL) and compound 1 to a clean flask and agitating for 15 min. Compound 1 dissolved in the MeSOsH solution. If all of the mixture did not dissolve, it was heated to 30 0 C to give complete dissolution. The vessel was charged with EtOAc (500 mL) and agitated for a further 30 min. The EtOAc layer was removed and the acidic reaction mixture was neutralized to pH 7 with 2M KOH aqueous solution. A light brown precipitate formed. The mixture was filtered, washed with H 2 O (1000 mL) and dried in a vacuum oven at 50 0 C to constant weight yielding compound 1 in crystal form B. If 1 H NMR indicated the presence of potassium methanesulfonate, it was removed by a slurry in H 2 O (20 volumes).
  • crystal form B was prepared by charging a 100 mL round bottom flask with compound 1 (5.17 g), acetic acid (20 mL) and water (30 mL) at room temperature. The resultant slurry was stirred at room temperature for 6 h. The mixture was filtered and washed with 0.5 N ammonium hydroxide followed by water. The product was dried under vacuum to yield 5.00 g (96.7%) of the crystal form B of 1.
  • Crystal form B was characterized by XRPD, DSC, and TGA.
  • FIG. 2A shows an XRPD trace of crystal form B.
  • the XRPD pattern of crystal form B is characterized by peaks at 2 ⁇ of 7.64°, 10.70°, 12.23°, 13.17°, 15.24°, 16.50°, 17.82°, 18.50°, 19.49°, 20.52°, 21.46°, 22.25°, 22.79°, 24.25°, 26.50°, 27.33°, and 28.43°.
  • FIG. 2B shows a DSC thermogram for crystal form B.
  • Crystal form B shows a minimum in DSC thermograms (i.e., melting point) at about 229 0 C, with a ⁇ H f of 141.1 J/g.
  • FIG. 2C shows a TGA trace for crystal form B. TGA revealed that form B was substantially free of solvent; weight loss from ambient temperature to 220 0 C was 0.8 %w/w.
  • FIG. 3A shows the XRPD trace of Form D, which is characterized by peaks at 2 ⁇ of 8.49°, 9.00°, 9.55°, 11.85°, 14.04°, 15.01°, 15.78°, 17.13°, 18.13°, 19.21°, 19.50°, 20.20°, 23.14°, 24.23°, 24.51°, 26.46°, and 26.81°.
  • FIG. 3B shows a TGA trace for crystal form D.
  • FIG. 3 C shows variable temperature XRPD traces of crystal form D. Traces (from bottom to top) were recorded at ambient temperature, 50 0 C, 65 0 C, 115 0 C, 140 0 C, 170 0 C, after cooling to 140 0 C, and after cooling to 30 0 C. The final product was crystal form A.
  • Example 8 Characterization of Crystal Form E ofl (1,4-dioxane solvate)
  • a sample of 1 in crystal form E was prepared by recrystallization from 1,4- dioxane.
  • the sample was characterized by XRPD, DSC, and TGA.
  • FIG. 4A shows an XRPD trace of crystal form E.
  • the XRPD pattern of crystal form E is characterized by peaks at 2 ⁇ of 8.49 °, 8.84°, 9.50°, 11.60°, 13.73°, 14.99°, 15.56°, 16.95°, 17.77°, 19.03°, 19.96°, 22.70°, 23.83°, 24.05°, 25.51°, and 26.57°.
  • FIG. 4B shows a DSC thermogram for crystal form E.
  • DSC thermograms of crystal form E show a desolvation endotherm above 123 0 C, and a minimum in (i.e., melting point) at about 244 0 C.
  • the melting point of desolvated form E suggests that form E converts to form A upon desolvation.
  • FIG. 4C shows a TGA trace for crystal form E. TGA revealed that form E lost
  • Example 9 Characterization of Crystal Form F ofl (methyl ethyl ketone solvate)
  • a sample of 1 in crystal form F was prepared by recrystallization from methyl ethyl ketone (MEK).
  • MEK methyl ethyl ketone
  • FIG. 5A shows an XRPD trace of crystal form F.
  • the XRPD pattern of crystal form F is characterized by peaks at 2 ⁇ of 8.44°, 8.78°, 9.48°, 11.60°, 13.66°, 14.94°, 15.43°, 17.00°, 17.70°, 18.94°, 19.76°, 20.00°, 22.35°, 23.83°, 25.40°, 25.62°, 26.26°, and 26.68°.
  • DSC thermograms of crystal form E show a desolvation endotherm above 102 0 C, and a minimum in (i.e., melting point) at about 240 0 C.
  • the melting point of desolvated form F suggests that form F converts to form A upon desolvation.
  • FIG. 6A shows an XRPD trace of crystal form G.
  • the XRPD pattern of crystal form G is characterized by peaks at 2 ⁇ of 4.66°, 6.56°, 10.06°, 10.81°, 12.00°, 13.31°, 14.74°, 16.00°, 16.51°, 17.40°, 18.79°, 19.56°, 20.31°, 21.71°, and 22.59°.
  • FIG. 6B shows a DSC thermogram for crystal form G.
  • DSC thermograms of crystal form G show a desolvation endotherm above 84 0 C, and a minimum in (i.e., melting point) at about 241 0 C.
  • the melting point of desolvated form G suggests that form G converts to form A upon desolvation.
  • FIG. 6C shows a TGA trace for crystal form G.
  • TGA revealed that form G lost 40% of its weight upon heating from ambient temperature to 50 0 C, or 1.3 moles solvent per mole of 1, consistent with form G being a hexafluoroisopropanol solvate.
  • FIG. 6D shows variable temperature XRPD traces of crystal form G. Traces (from bottom to top) were recorded at ambient temperature, 25 0 C, 70 0 C, 100 0 C, 120 0 C, 210 0 C, 220 0 C, 230 0 C, 235°C, and 240 0 C. Note that the traces recorded above 200 0 C showed additional signals due to the presence of a protective semi-transparent dome. The final product was crystal form B.
  • the vials were capped and placed in a shaking incubator which cycled between ambient temperature and 50 0 C, changing every 12 hours. Shaking was continued for 4 days. Inspection of the vials showed that the majority of the 1,1,1,3,3,3- hexafluoropropan-2-ol had evaporated, so an additional 500 ⁇ L was added. Inspection after another 2 days showed that this vial now contained only a solution, so additional solid ( ⁇ 30mg) was added.
  • FIG. 7A shows the XRPD trace of Form H, which is characterized by peaks at 2 ⁇ of 8.40°, 8.82°, 9.33°, 13.67°, 14.21°, 14.74°, 15.43°, 16.88°, 17.88°, 19.06°, 19.73°, 23.96°, 25.36°, 25.99°, and 26.45°.
  • FIG. 7B shows a TGA trace for crystal form H. TGA revealed that form H lost 38% of its weight upon heating from ambient temperature to 150 0 C, consistent with form H being a THF hemisolvate.
  • the relative stabilities of the forms A and B was determined by a vapour diffusion experiment. Approximately equal amounts of the two forms were ground together to produce an intimate mixture. The mixture was packed into a silicon 510-cut recessed wafer XRPD holder and the XRPD of the mixture determined. The holder was then placed in a covered dish containing NMP (a known solvent 1) at room temperature. The mixture was re-examined from time to time to monitor any changes in the XRPD pattern.
  • NMP a known solvent 1
  • FIG. 8 shows that over time the peaks characteristic of Form B diminish, disappearing complete by the 23 day time point. This indicated that at room temperature, Form A was the more stable polymorph.
  • the traces from bottom to top in FIG. 8 were recorded initially, at 24 hours, at 3 days, at 1 week, at 10 days, and at 23 days; the topmost traces are a form A reference and a form B reference.
  • Example 14 Relative Stability of Forms D and H Forms D and H are both THF solvates and appear to have similar stoichiometry.
  • the relative stabilities of Forms D and H was investigated by a vapour diffusion experiment. Approximately equal amounts of the two forms were combined to produce an intimate mixture. The mixture was packed into a silicon XRPD holder and the XRPD of the mixture determined. The holder was then placed in a covered dish containing THF:NMP approx. 90:10 v/v at room temperature. The mixture was re-examined from time to time to monitor any changes in the XRPD pattern.
  • the structure was solved using the global optimization methodology implemented in the program DASH, using diffraction data collected to a resolution of ⁇ 2 A. The structure obtained was consistent with the diffraction data and the presence of a small degree of preferred orientation in the sample was detected and allowed for. Table 1 presents the atomic coordinates of form A.
  • FIG. 9 shows three views of 1 in form A based on the crystal structure: at top, the full structure; at bottom left, hydrogen bonding involving Nl and N6; at bottom right, hydrogen bonding involving N7, N2 and N6.
  • Example 16 Crystal Structure of Form B
  • the structure was solved using the global optimization methodology implemented in the program DASH, using diffraction data collected to a resolution of ⁇ 2 A. The structure obtained was consistent with the diffraction data. No preferred orientation was detected in the sample. Table 2 presents the atomic coordinates of form B.
  • FIG. 10 shows three views of 1 in form B based on the crystal structure: at top, the full structure; at bottom left, hydrogen bonding involving N2 and N6; at bottom right, hydrogen bonding involving N7 and Nl.
  • a comparison of FIGS. 9 and 10 highlights differences in the molecular conformation observed in the two forms with respect to the orientation of ring (C6-C7- C8-C9-C10-C11). Compare, e.g., the position of methyl carbon C12 in FIGS. 9 and 10.
  • forms 1 and 2 have in common the dimer motif (i.e., hydrogen bonding involving a pyrimidine nitrogen and the 5-amino group (N6)) and a propensity for face-to-face close-packing of planar ring structures.
  • dimer motif i.e., hydrogen bonding involving a pyrimidine nitrogen and the 5-amino group (N6)
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